Genetic Heart Risk Shared by Millions; Experimental Drug Offers Potential Life-Saving Breakthrough
In a significant step forward for cardiovascular health, Eli Lilly is currently conducting a Phase 3 clinical trial for lepodisiran, an investigational treatment aimed at significantly reducing high lipoprotein(a) [Lp(a)] levels, a recognized cardiovascular risk factor.
The trial, which began in mid-2025, is actively underway and aims to determine whether the substantial reduction in Lp(a) seen in earlier studies translates into a decrease in cardiovascular events such as heart attacks.
The Phase 2 ALPACA trial, which involved over 300 people genetically predisposed to high levels of Lp(a), demonstrated that lepodisiran reduces Lp(a) levels by more than 90% at six months. This is considered very promising in addressing genetically elevated Lp(a).
However, while Lp(a) levels drop significantly, the clinical benefit in reducing cardiovascular events remains to be proven. The Phase 3 trial is essential to establish these outcomes.
The trial addresses previous limitations by enrolling a more diverse patient population, including more Black participants who are disproportionately affected by elevated Lp(a). Positive results from this Phase 3 trial are expected to be pivotal for regulatory approval and potential market introduction.
Lepodisiran works by inhibiting the liver's production of apolipoprotein(a), a key component of Lp(a). People who received two subcutaneous injections of lepodisiran at the start of the study and six months later saw a 95% reduction in Lp(a) a year later. Those given only a single injection of the highest dose had an overall 88% reduction in Lp(a) a year later, and people on the highest doses saw a drastic 94% reduction in Lp(a) by the six-month mark.
Eric Brandt, director of preventive cardiology at the University of Michigan Health Frankel Cardiovascular Center, expressed excitement about the drug's future. "This could be a game-changer for people with high Lp(a) levels," he said.
In 2021, the Food and Drug Administration approved Alnylam Pharmaceuticals and Novartis' Leqvio as a LDL-lowering treatment for people with certain genetic conditions or poorly controlled atherosclerosis. However, lepodisiran could soon become the first treatment of its kind for the common genetic risk factor of high Lp(a).
Eli Lilly has started to enroll volunteers for its Phase 3 trial of lepodisiran. The precise timeline for trial completion and results disclosure has not been publicly detailed but is anticipated to be a critical milestone for this novel therapy in the near future.
[1] Eli Lilly and Company. (2025). Lilly Announces Positive Topline Results from the Phase 2 ALPACA Trial of Lepodisiran in Patients with High Lipoprotein(a). Retrieved from https://www.lilly.com/news/releases/2025/lilly-announces-positive-topline-results-from-the-phase-2-alpaca-trial-of-lepodisiran-in-patients-with-high-lipoprotein.html
[2] New England Journal of Medicine. (2025). Lepodisiran for the Treatment of High Lipoprotein(a). Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2505482
[3] American Heart Association. (2025). Lilly's Lepodisiran Shows Promise in Lowering Lipoprotein(a) Levels. Retrieved from https://www.heart.org/en/news/2025/08/15/lillys-lepodisiran-shows-promise-in-lowering-lipoprotein-a-levels
[4] Fierce Pharma. (2025). Eli Lilly's lepodisiran trial for high lipoprotein(a) gets a boost from promising Phase 2 data. Retrieved from https://www.fiercepharma.com/research/eli-lillys-lepodisiran-trial-for-high-lipoprotein-a-gets-a-boost-from-promising-phase-2-data
[5] STAT News. (2025). Eli Lilly's lepodisiran trial for high Lp(a) begins enrolling patients. Retrieved from https://www.statnews.com/pharmaceuticals/2025/06/02/eli-lillys-lepodisiran-trial-for-high-lp-a-begins-enrolling-patients/
